Melanoma, a malignant neoplasm of melanocytes, is the most deadly form of skin cancer (Chudnovsky et al., 2005). The incidence of melanoma continues to increase despite public health initiatives to promote protection against sun's harmful effects. In Europe, approximately 26,100 males and 33,300 females are diagnosed each year with melanoma, and around 8,300 males and 7,600 females die of it. It is the eighth most commonly diagnosed cancer in females and seventeenth in males. Light skin type, large numbers of nevi and excessive sun exposure, mainly in childhood, are the major modifiers of melanoma risk (Houghon and Polsky, 2002). When melanoma is detected in its early stages it is curable, but once advanced it is very difficult to treat. The primary lesions are located in limbs (22%), trunk (40%), head and neck (15%), and 16% in unknown sites (Capizzi and Donohue, 1994). The most common sites of metastases found in the autopsy are skin and subcutaneous tissue (75%), lung (70%), liver (68%), small intestine (58%), pancreas (53%), heart (49%), brain (39%) and spleen (36%). With visceral metastasis, the 5-year survival drops to approximately 6%, and the median survival from time of diagnosis is 7.5 months (Barth et al., 1995).
The increasing incidence of melanoma and its poor prognosis in advanced stages justify the investigation into novel approaches of prevention, such as chemoprevention, which has been used to reduce the incidence of other cancers. Ideally, medications would be inexpensive, easily administered, and have minimal side effects. Such agents would be especially valuable for high risk patients. In the evaluation of effectiveness, chemoprevention interventions would best be measured by their ability to reduce melanoma incidence and melanoma mortality. Investigation into a possible role in melanoma chemoprevention continues for multiple agents, including sunscreen, lipid-lowering medications, non-steroidal anti-inflammatory drugs, dietary nutrients, immunomodulators, and other drugs, including retinoids, difluoromethylornithine, and T4 endonuclease V (Francis et al., 2006). Although chemoprevention is the ideal strategy, primary melanoma, once formed, should be surgically removed and chemotherapy focuses in metastasis control. At present, limited therapeutic options exist for patients with metastatic melanoma, and all standard combinations used in metastasis therapy have a low efficacy and poor response rates (Koon and Atkins, 2006).
One example of the complications involved in melanoma chemotherapy is the limited use of antifolates. Although methotrexate (MTX), the most frequently used antifolate, is an efficient drug for several types of cancer it is not active against melanoma (Kufe et al. 1980). It is, therefore, of great interest to develop a second generation of antifolate drugs to overcome, these problems and which should present low toxicity for the prophylaxis and treatment of melanoma.